4.8 Article

N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Journal

CELL
Volume 184, Issue 9, Pages 2332-+

Publisher

CELL PRESS
DOI: 10.1016/j.cell.2021.03.028

Keywords

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Funding

  1. National Institute of General Medical Sciences [R01GM120553]
  2. National Institute of Allergy and Infectious Diseases [DP1AI158186, HHSN272201700059C]
  3. Pew Biomedical Scholars Award
  4. Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund
  5. Fast Grants
  6. Natural Sciences and Engineering Research Council of Canada
  7. Pasteur Institute
  8. University of Washington Arnold and Mabel Beckman cryo-EM center
  9. Advanced Light Source, a US DOE Office of Science User Facility [DE-AC02-05CH11231]

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The study identifies 41 human monoclonal antibodies that recognize the N-terminal domain of the SARS-CoV-2 spike protein and exhibit strong neutralizing activity. These antibodies inhibit cell-to-cell fusion, activate effector functions, and protect animals from virus challenge, highlighting the importance of NTD-specific neutralizing antibodies for protective immunity and vaccine development. Several SARS-CoV-2 variants with mutations in the NTD supersite suggest ongoing selective pressure on the virus.
The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARSCoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.

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